12q21.3-q23 (Yandava et al., 1999). Plus strand.

CIS2,Cish2,SOCS-2,SSI-2,SSI2,STATI2

Neural development

SOCS2 plays a critical role in neuronal development, growth, and stem cell differentiation (Turnley et al., 2002).

Inflammation

SOCS2 deficient dendritic cells and macrophages are hyper-responsive to microbial stimulation. SOCS2 deficient animals have uncontrolled production of inflammatory cytokines (IL-12, IFNγand TNFα ) and succumb to endotoxic shock, polymicrobial sepsis and other microbial infections (Esper et al., 2012). SOCS2 plays a central role in differentiation and maturation of innate immune cells. Specifically, SOCS2 promotes generation of regulatory dendritic cells and macrophages (Novak et al., 1999; Jackson et al., 2004; Hu et al., 2012) and Treg population (Knosp et al., 2013). Conversely, SOCS2 inhibits Th2 differentiation (Knosp et al., 2011). Upon induced inflammatory challenge, absence of SOCS2 has been shown to render multiple immune cell types incapable of mounting anti-inflammatory responses. Under resting conditions, SOCS2 null animals also display a population-bias towards a pro-inflammatory phenotype (Machado et al., 2006; Lee et al., 2010; Knosp et al., 2011; Posselt et al., 2011; Hu et al., 2012).
SOCS2 is known to inhibit TGFβ, IL-4, IL-5, IL-10, IL-13 and IFNγ signaling (Knosp et al., 2011, Knosp et al., 2013). In general, SOCS2 inhibits expression/secretion of pro-inflammatory cytokines and promotes generation of regulatory phenotype (anti-inflammatory) of immune cells. SOCS2 is thought to function in both MyD88 dependent and independent TLR4 signaling pathways because its downregulation negatively affects SAPK/JNK, p38 MAPK, ERK and NFkB signaling (Hu et al., 2009b). Being an E3 ligase, SOCS2 regulates a number of proteins highly implicated in regulation of immune responses such as FoxP3 (Knosp et al., 2013) and TRAF6 (McBerry et al., 2012). SOCS2 also accelerates degradation of other members of the SOCS family such as SOCS1 and SOCS3 thus further impinging on downstream STAT signaling (Piessevaux et al., 2006; Tannahill et al., 2005). In turn, SOCS2 gene itself is under regulation of various inflammatory signals (e.g., LPS, dioxins, LipoxinA4) (Machado et al., 2006; Hu et al., 2009b, 2012) and cytokines (e.g.,IL-4, IL-10, IFNβ, IFNγ) (Knosp et al., 2011; Posselt et al., 2011).

Breast cancer

SOCS2 expression inversely correlates with histological grades and is a positive prognostic factor (Farabegoli et al., 2005; Haffner et al., 2007). SOCS2 expression is induced by estrogen receptor (ER) activity. Estrogen treatment activates ER which in turn upregulates miR-191 which through downregulation of SATB1, a global chromatic remodeller, enhances SOCS2 transcription (Nagpal et al., 2013). Upregulation of SOCS2 upon estrogen administration antagonizes growth hormone action mediated through JAK2/STAT3 and STAT5 (Leung et al., 2003).

Colon cancer

Both heterozygous and homozygous deletions of SOCS2 promoted spontaneous tumorigenesis in ApcMin/+ mice model of colorectal cancer. This is accompanied with a dramatic increase in AP-1 DNA binding (Newton et al., 2010). Acromegalic patients are prone to colonic polyp formation. These patients with hyperplastic polyps have increased SOCS2 transcripts (Bogazzi et al., 2009).

Myeloproliferative disorder

SOCS2 gene is also hypermethylated in myeloproliferative disorders (Zhou et al., 2009; Zhang et al., 2013). SOCS2 is an important negative regulator of a constitutive active mutant of JAK2 (JAK2 V617F) (Etienne et al., 2007).

Prostate cancer

SOCS2 is upregulated at both mRNA and protein levels in primary prostate cancer tissues relative to normal prostate. This upregulation is correlated to lower Gleason score, absence of metastasis and low PSA failure (Zhu et al., 2013). In contrast, SOCS2 expression is downregulated in castration resistant prostate cancer. This is partly explained by the fact that SOCS2 is transcriptionally upregulated by androgen receptor and inhibits GH signaling in prostate (Iglesias-Gato et al., 2014).

Other cancers

SOCS2 gene is hypermethylated in melanoma and ovarian carcinoma (Marini et al., 2006; Liu et al., 2008). Lower SOCS2 expressions are also correlated to higher grades of hepatocellular carcinoma (Qiu et al., 2013).

Gigantism

SOCS2 null mice are giants but not obese (Metcalf et al., 2000). SOCS2 deficient mice have growth and metabolic characteristics that can be related to the enhanced GH actions (Rico-Bautista et al., 2005). On the other hand, the gigantic phenotype displayed by SOCS2 null mice is mechanistically different from that of human acromegalic patients as they do not exhibit increased circulating IGF-1 levels and seems to express reduced levels of GH (Greenhalgh 2005 and Zadjali 2012).

Gigantism is a condition characterized by excessive growth, significantly above average. This is caused due to an overactivation of growth hormone signaling.

Diabetes

Genomic linkage analysis identified SOCS2 as a susceptibility gene for type 2 diabetes in a cohort of Japanese individuals. In the same study, adenovirus-mediated expression of the SOCS2 gene in MIN6 cells or isolated rat islets significantly suppressed glucose-stimulated insulin secretion (Kato et al., 2006). Constitutive SOCS2 expression in mice pancreatic beta cells interferes with proinsulin processing and leads to decreased insulin secretion (Lebrun et al., 2010). In contrast, SOCS2 null mice does not exhibit obvious defects in pancreatic beta cell function. When challenged with high fat diet SOCS2 null mice are protected from hepatic steatosis but exhibit an exacerbated inflammatory response and a worsening of insulin sensitivity as compared to wild-type mice on a similar diet.

Diabetes is a condition characterized by high blood sugar levels. This is caused due to inadequate insulin production or insulin resistance.

Osteoarthritis

Analysis of SOCS2 null mice has revealed that the absence of SOCS2 induces a reduction in the trabecular and cortical volumetric bone mineral density (Lorentzon et al., 2005). SOCS2 induces the differentiation of C2C12 mesenchymal cells into myoblasts or osteoblasts (Ouyang et al., 2006).

Osteoarthritis is a condition characterized by mechanical degeneration of joints resulting in pain and restricted movement. This is caused due to hereditary and metabolic reasons.